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Intravenous immunoglobulin (IVIg), one of the most powerful weapons in the pharmaceutical arsenal against autoimmune disorders, may precipitate strokes in elderly patients with other stroke risk factors, warn authors of a study at Wake Forest University School of Medicine in Winston-Salem, NC.

Lead author James B. Caress, MD, Assistant Professor of Neurology, reported clinical features of 16 patients who suffered strokes after receiving infusions of IVIg – 14 within 24 hours after treatment or during administration. The remaining patients suffered strokes within four days after completing treatment. Results of the study, a retrospective review of patient cases at Wake Forest University Baptist Medical Center (WFUBMC) and other regional medical centers, were published in Neurology (2003;60:1822–1824).

Fifteen of the 16 patients had one or more risk factors for stroke, which included hypertension, diabetes mellitus, and previously known asymptomatic cerebrovascular disease or stroke.

The Wake Forest medical center treated 498 different individuals with IVIg as in-patients during the four-year period. Only three of the 16 who had strokes after IVIg were in-patients when they were treated.

CONDITIONS TREATED

Fully half of the patients, whose average age was 66 years, were undergoing IVIg treatment for the first time. Ten patients were being treated for neuromuscular conditions – such as chronic inflammatory demyelinating polyneuropathy, autoimmune cerebellar ataxia syndrome, and multifocal motor neuropathy – while the remaining six had hematological indications, such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and chronic lymphocytic leukemia.

Nine of the patients suffered multifocal infarctions, said Dr. Caress, and 14 suffered strokes involving the cerebral or cerebellar cortex. Only one stroke was fatal. Imaging showed all strokes were acute events; none were hemorrhagic.

“There have been sporadic reports of stroke following IVIg in the past, but this is the first time we have been able to document actual clinical features of these patients,” Dr. Caress said.

“I think twice before prescribing IVIg to those with known carotid disease, prior strokes or myocardial infarctions, and those with extremely elevated platelet counts,” he continued. “Our finding that half of the patients were receiving their first course of IVIg may suggest that close observation is warranted for transient neurologic symptoms during the first course of IVIg therapy.”

DATA ARE ANECDOTAL

Dr. Caress noted that the collection of data was anecdotal and not systematic. “We did make attempts to identify all cases at WFUBMC but could have missed a few. I believe there was some lack of awareness that this could happen despite scattered case reports since 1986, so physicians may have missed the connection at times. Since half of our cases were reported from community physicians, and not just from a tertiary care center where we might have more older, sicker patients, I see no reason why this series is ‘special’ in a way that might lead to over-representation of this complication.”

As a percentage of several hundred patients treated with IVIg at the centers over the four-year period, the 16 events represented a 0.6-percent value and may in fact overestimate risk because they were older and hospitalized, and more likely to have stroke risks, he added.

“But this is not a true incidence or prevalence,” said Dr. Caress. “Many of these 498 were treated with multiple IVIg courses during this time but only got counted once. Thirteen of the 16 were at other hospitals, WFUBMC day hospital or clinics, or at home. I could not get an accurate denominator for anything except true in-patients at WFUBMC.”

RISK UNDERESTIMATED

“The study seems to show that stroke happens more often than people thought during treatment with IVIg. While most of the people who suffered stroke had one or more stroke risk factors, without a control group we could not prove that those conditions in fact put them at higher risk. However, the data might actually underestimate the risk because our information was collected retrospectively and nonsystematically rather than by reviewing discharge data of prospective sampling,” he noted.

“Also, mild strokes or [transient ischemic attacks] may have not been detected. Unfortunately, our method of sampling precludes determination of whether any specific characteristic of IVIg administration might be more risky than others for such patients.”

He added that because half of the stroke patients were receiving IVIg for the first time, there might be as yet unidentified intrinsic factors in certain patients that put them at greater risk.

All but one patient had at least one concomitant risk factor for stroke, explained Dr. Caress, such as hypertension, diabetes mellitus, blood disorders associated with stroke, recognized asymptomatic cerebrovascular disease, or prior history of stroke.

Patients were treated with anticoagulants, thrombolytics, and anti-platelet agents, although Dr. Caress noted that the most appropriate treatment has yet to be determined. Prior studies have suggested a number of possible factors that might be associated with stroke risk in IVIg recipients. These include modest elevation in serum viscosity, rapid change in viscosity, sudden intravascular compartment expansion, cerebral arterial vasospasm, and introduction of vasoactive cytokines or clotting factors.

FURTHER RESEARCH NEEDED

“While the percentage of patients suffering stroke as a result of IVIg is small, the results of our study indicate further research should be taken to improve our understanding of why strokes occur following treatment so that we can identify patients at high risk and prevent this complication,” said Dr. Caress.

“I don't think widespread screening such as carotid ultrasound, or pretreatment, for instance with aspirin, can be recommended at this point. Screening for IgA deficiency is standard but has nothing to do with stroke.”

ADDITIONAL PERSPECTIVE

In an accompanying editorial, Marinos C. Dalakas, MD, Chief of the Neuromuscular Disease Section of the National Institute of Neurological Disorders and Stroke (NINDS), noted that while there have been adverse reactions to therapy over the years, IVIg has an “excellent” safety record.

“This is an extremely rare phenomenon, but it does happen,” he told Neurology Today in a phone interview. “Why there were these 16 cases at one hospital is sort of a mystery to me. It's unclear if these patients were all treated on-site or were receiving home care infusions. You need to be very careful about home care infusions. I believe they should be performed at a hospital. Sometimes IVIg patients do well at the hospital but once they start receiving home care infusions, things start going wrong. It's very important that these patients are monitored.”

Dr. Dalakas noted that no strokes have been associated with IVIg therapy in nearly 700 patients enrolled in NINDS supported clinical trials for neuropathies or myopathies. But, he added, neurologic patients may be more prone to strokes due to muscle weakness, development of silent clots, or subclinical hypercoagulable states, especially cardiovascular patients.

“It's important to identify patients at risk,” he stressed. “This includes elderly patients who have diabetes, hypercholesterolemia, hyperfibrinogenemia, or hypergammaglobulinemia, and especially patients who have been immobilized for long periods, such as wheelchair patients.”

SUGGESTED PRECAUTIONS

Dr. Dalakas recommended measuring viscosity before infusion and lowering it if high. A slow rate of infusion is vital for such patients, while ultrasound can be used to search for peripheral clots in the extremities of long-term immobilized patients. Whether administering the anticoagulant heparin might help avert such events is unknown, he added.

“Physicians need to be aware that a small population of patients may be at increased risk and monitor them carefully, and that is the purpose of my editorial – to educate them. But this isn't new information. My first paper on the subject was published in 1994” (Neurology 1994;44:223–226).

While there is no specific treatment for thrombi dislodged or triggered by IVIg administration, cerebral angiography may help identify at-risk patients, said Dr. Dalakas. Some patients have improved with anticoagulants, notably tissue plasminogen activator (tPA), however timing is crucial and tPA therapy carries other risks, he noted.

In the same issue of Neurology Daren Okuda, MD, and Kumaraswamy Sivakumar, MD, of the Barrow Neurological Institute at St. Joseph's Hospital in Phoenix, AZ, reported successfully using tPA to treat three of four IVIg patients who experienced cerebral or peripheral arterial thrombosis (Neurology 2003;60:1825–1826).

ARTICLE IN BRIEF:

✓ A retrospective study of patients at Wake Forest University Baptist Medical Center found that intravenous immunoglobulin (IVIg) may precipitate strokes in elderly patients with other stroke risk factors.

The study author and another expert agree that neurologists need to be aware that a small population of patients who receive IVIg are at increased risk for strokes and should be monitored carefully.

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